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Thrombolysis in ischemic stroke

- a clinical challenge

Grethe AndersenDepartment of NeurologyÅrhus University Hospital

Ischemic stroke – worst case!

Left-sided hemiplegia, sensory deficits, hemianopia and neglect.

Komplications: depression, centrale pain, epilepsy.

Survivors: 3-6 months of rehabilitation/nursing home.

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Facts about stroke

• Incidence: 2 pr 1000 first ever strokes in Scandinavian countries. – 50% symptom remission within 1 week– 25% disabled with need of rehabilitation for 1-3

months– 25% severe disabled or dead within 3 months

• The most severe strokes are admitted earliest• The effect of thrombolysis declines with time

from symptom onset

Prove of thrombolysis (2002) was conditioned - SITS-MOST and ECASS-3 were requiered

mRS 0-1 at day 90

Adjusted odds ratio with 95 % confidence interval by stroke onset to treatment time (OTT)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Adj

ust e

dod

dsra

tio

Stroke onset to treatment time (OTT) [min]

60 90 120 150 180 210 240 270 300 330 360

< 3 hSITS-MOST

3-4 hRCT

ECASS III

> 4,5h

except selected patients

Brott TG. International Stroke Conference 2002; abstract.

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Meta-analysis of rt-PA studies ECASS, NINDS, ATLANTIS2.775 randomized patients < 6 h

Lancet 2004;363:768-74.

3 months follow-up

Good outcome (mRS 0-1) vs. poor outcome (mRS 2-6)

Region Midt

1,2 mill. inhabitants (20% of DK)2.400 ischemic strokes per year

Organisation:Acute stroke admission directly in neurological department Århus

- first 2 years in day-time- from 01.04.06 round-the clock

- 01.11.06 telestroke service in

Holstebro

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Before arrival at Århus University Hospital

On call thombolysis neurologist8949 4444

”Ambulance-criteria”Inclusion criteria:• Onset time < 3 hours• age 18 – 80 • Independent ADL• Paresis and/or

dysphasia or other symptoms suggesting stroke

General Practitioner

Casuality department

Ambulance param.

Call First priority ambulance transport

Department of neurology

+1.5T MRIEvaluation

Pre-hospital phase

Highest priority ambulance transport to Department of neurology – stroke ward

Admission

•Neurological examination – NIHSS

•Exclusion criteria

•ECG, BP, Tp., Lab. -tests

AcuteMRI

ICH

DWI lesion and 1<NIHSS<25

DWI > ½ ofMCA area

Thrombolysis(SITS-MOST)

0-3 hours

3-4 hours

AcuteCT

Thrombolysis(RCT: ECASS 3)

DWI > 1/3 of MCA areaand = PWI

•Transfer to regional stroke department/ Dept. of Neurology

•Inclusion in scientific studies or RCT

•Further cerebrovascular exam. (Ecco, US etc.) and rehabilitation

MRI/ CT

•Symptom progression

•24 hours

Patient admission

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The Acute Stroke StudyResults from the first 100 cases (80% MRI)

46%

26%

14%

2%

12% ischemicinfarctTIA

ICH

Tumors

Other

ThrombolysisÅrhus: April 2004 - Oktober 2006

47

9 97

10 11 11

27

32

0

5

10

15

20

25

30

35

40

2. kv

artal

3. kv

artal

4.kva

rtal

1.kva

rtal

2. kv

artal

3. kv

artal

4.kva

rtal

1.kva

rtal

2. kv

artal

3. kv

artal

2004 2005 2006

5%

10%

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Thrombolysisjan. – okt. 2006

• 1170 patients admitted for stroke– 703 stroke (60%)

• 460 ischemic stroke• 153 TCI• 90 ICH, SAH, SDH, EDH

• 187 patients admitted for acute thrombolysis – 70 treated with thrombolysis

• 6% of all patients admitted for stroke• 10% of all stroke patients• 15% of all patients with ischemic stroke• 37% of all patients admitted for acute thrombolysis

Time delay (minutes)

145153MedianOnset to

treatment/needle time

6668MedianDoor to needle

DNT

524MedianImaging study to report

time

2528MedianDoor to imaging study

time

6585MedianOnset to treating

hospital/door time

SITS-MOSTÅrhus

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Door-to-needle is inversely related to prehospital delay (onset-door)

Imaging details

788775869276Infarcts%

22122311719

No infarcts %

Follow-up24 timer

218715729315Infarcts%

7312 77307 82

No infarcts %

Akut skanning

CT or MR

99 %MR

10 %CT

93%

CT or MR

100%MR

73 % CT

30 %

SITS-MOSTÅrhus

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Stroke subgroups

12%10%I63.9 None of the above ( can be multiple causes)

5%7%I63.8 Other/unusual cause

9%16%I63.5 Small vessel disease (lacunar)

37%23%I63.4 Cardiac source of emboli

24%28%I63.3 Large vessel disease, other

13%17%I63.0 Large vessel disease with sign. Carotidpathology

SITS-MOST

Århus

Distribution of stroke severity in different studies

0-7 mild

8-14 moderate

NIHSS>14 severe

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Outcome after 3 monthsModified Rankin Scale 0(no symptoms) – 6(dead).

pooled analysis (Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC, Jr., Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials)

mRS 0

mRS 0

mRS 0

1

1

1

2

2

2

3

3

3

4

4

4

5

5

5

Døde

Døde

Døde

0% 20% 40% 60% 80% 100%

Århus

pooled analysis

SITS-MOST

All

Moderate

Mild

Severe

Responder analysis of outcome.

For mild stroke (NIHSS 0-7)good outcome is mRS 0

For moderate (NIHSS 8-14)good outc is mRS 0-1

For severe stroke (NIHSS >14)good outc is mRS 0-2

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ThrombolysisComplications:

2% Quinckes oedema1-5% Hypotension1-2% Epistaksis1-2% Symptomatic ICH

Safety Outcome Reports

11%11%Significant deterioration

14%8%Death within 3 month

1,7%1,4%SICH user defined

SITS-MOST

Århus

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Clinical dilemmasexamples

• Visitation• Indication• Medication• Follow up

clinical dilemmaVisitation

Case IPhone call from a regional hospital -Randers, emergency room60 year old man, former healthy, no medicationSudden left-sided hemiplegia while driving his car. Onset as a TIA, paramedics found the patient in his car unconscious ?

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Case I

Case I

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Clinical dilemmaIndication

Case II60 year old man

bypassop., hypertension, hyperkolesterolæmiaSudden onset of

DysphasiaRight sided facial paresis and dysartriaRight-sided senso-motor disability in arm

At admissionallmost complet recovery, NIHSS 0-1 (asymetric smile)

Case II

T2

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Case II

DWI

Case II

MR-angio

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Case II

PWI

Klinisk dilemmaIndikation

Case II• 5 minutes after MRI – symptoms starts

again (NIHSS 6)• It is now 3 hours and 10 minutes after

onset• What can we do?

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Case II

CT 3 hours and 20 minutes after onset

NIHSS: 6

Case II

CT 24 hours after onset

NIHSS: 3

MRS at 3 months: 0

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• The most common reason for exclusion from treatment is a: few symptoms or b: rapidly improvement of symptoms (58%)• Patients with more than 4 point recovery on NIHSS before rt-PA decision of no-treatment have significant worse outcome• Patients with stable symptoms were more likely to have small vessel infarction• 27% of those not treated were not discharged to home

Poor Outcomes in Patients Who Do Not Receive Intravenous Tissue Plasminogen Activator

Because of Mild or Improving Ischemic Stroke

Stroke 36(11), November 2005, pp 2497-2499

Clinical dilemmaMedication

Case III• 65 year old man with atrial fibrilation, not

treated with warferin• Sudden symptoms at 14.15.

– Left-sided hemiplegia and lower facialparesis. No forsed eye deviation

• Admitted 1 hour later: NIHSS 14 (severe stroke)

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Case III

DWI ADC

Case III

FlairDVI

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Case III

• Actilyse is started at kl. 16.20 (2 hours and 5 minutes after onset)

• BP rises during treatment (>150 mmHg systolisk)

• Thrombolysis is temporary stopped (iv. labetalol)

• 80% of full dose was given

Case III

8 hours after onset

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Case III

19 hoursafter onset

Bleeding complicationsSymptomatic bleedings – definitions RCT: • RCT: Parenchymal haematoma exceeding more than

30% of the infarct volume with significant space occupying effect

• SITS-MOST: Parenchymal haematoma and a significant woresning of symptoms or dead (increase in NIHSS of 4 points or more)

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Parenchymal haematoma 0-6 h. 1. Meta-analysis of rtPA studies: 2.775 ptt. < 6 h

2. SITS-MOST registre: 6.000 patients < 3 timer

symptomatic parenchymal bleeding: 1.7%

Klinisk dilemmaMedication

Case IV• 73 årig woman, DM type 2, hypertension• Sudden onset of:

– Dysphasia– Right-sided hemiplegia– NIHSS 11– BP > 230/110 mmHg

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Case IV

T2 DWI ADC

2 hours and 42 minutes after onset

Case IV

PWI

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Case IV

15 hoursafter onset

Case IV

19 hours after onset

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Case IV

• Audit– Start of treatment were 3 hours 15 minutes– 105 mg Actilyse (max dose is 90 mg)– Blodtryk 230/110 mmHg not sufficiently

treated before and after actilyse treatment.

Clinical dilemmaFollow up

• Case V• 63 year old former healthy male• Sudden onset of

– Dysphasia– Right-sided hemiplegia

• NIHSS 16

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Case V

CT 150 minutes after onset

Case V

• Actilyse treatment starts at 3 hours after onset

• Dramatic recovery after about 1 hour• No complications• NIHSS: 5 after 24 hours• Aspirin was started and the patient

discharged to his regional hospital

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Case V

MR 24 hours after thrombolysis

Case V

MR-angio before treatment

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Case V2 days later

Admitted again with severe stroke i left MCA (NIHSS ~18)

Conclusion• Treatment must be performed by a physician trained in

neurological care and experienced in the use of thrombolytic treatment (NICE guidelines)

• Thrombolysis requiers careful– Visitation– Indication– Medication– Follow up

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Future• MRI mismatch will probably replace “clinical” onset-to-

treatment window (DIAS, DEFUSE, EPITET).– Age limit 80 years ? (1/3 of stroke patients)

• I.a. thrombolysis +/- thrombectomi are advancing technologies.

• Clot lysis facilitation with transcranial ultrasound.• Other acute treatments for stroke e.g. Novo-7 for ICH.• In a modern society the stroke patient will demand acute

stroke settings with a hyperacute diagnostic setup and treatment on individual basis.

Time is Brain

Imaging delay in patients with suspected stroke (ending with other diagnoses)

After the introduction of thrombolysis (stage II) a larer proportion of patients are scanned within the very early hours of hospitalization

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Length of stay in SU for patients with suspected stroke (ending with non-stroke diagnoses)

LOS significantlyshortened after intro of rtPA (stage II)

Fast triage of non-stroke patients to appropriate departments or to discharge.

Total length of hospitalization for patients with suspected stroke (ending with non-stroke diagnoses)

Total LOS was shortened from stage I-III.

Fast triage of non-stroke patients to appropriate departments or to discharge.